Neuropathic Pain

Amanda Macone, MD; James A. D. Otis, MD, FAAN, DABPM


Semin Neurol. 2018;38(6):644-653. 

In This Article

Topical Agents

Topical agents can be a useful adjunctive agent in the management of neuropathic pain, as their action is local rather than systemic, providing relief in pain secondary to a peripheral etiology.[67] Topical agents alone are usually insufficient to produce total pain relief, but they can be helpful in patients who experience adverse effects from other drugs. Capsaicin, a naturally occurring pepper extract, has been found to be useful in reducing neuropathic pain in diabetics.[67] Capsaicin is applied to the area of greatest discomfort several times a day, but pain relief does not occur for several days. On initial application, many patients complain of markedly worsened pain and burning. While the burning pain resolves after multiple applications, the burning can be severe, and patients often are not able to tolerate it. Furthermore, multiple studies have demonstrated capsaicin has weak to moderate efficacy for neuropathic pain.[68] It should be reserved for combination therapy, or when typical analgesics have failed. In a study of 200 patients with chronic neuropathic pain, pain was significantly reduced by the combination of topical 3.3% doxepin and 0.025% capsaicin. Absolute pain reduction was similar to either agent alone, but with a more rapid onset with the combination.[69] Qutenza, an 8% capsaicin dermal patch, has demonstrated promising effects in painful neuropathies.[70,71] Specifically, according to a 2008 study by Simpson et al, Qutenza revealed promise in treating HIV neuropathy, which is typically nonresponsive to many other treatments and medications.[72] A double-blind, randomized, placebo-controlled 3-week study evaluated the efficacy of topical 2% amitriptyline, 1% ketamine, and a combination of both in treating patients with diabetic neuropathy, postherpetic neuralgia, or postsurgical/posttraumatic neuropathic pain. The study used pain assays of change in average daily pain intensity (baseline week vs. final week: an 11-point scale) and the McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction. It was demonstrated that 2% amitriptyline, 1% ketamine, and the combination all produced a good response across all pain scales.[73] Additional open-label studies demonstrated greater pain relief with increased concentrations of drug, but no increase in side effects.

Transdermal lidocaine patch use has become popular as a treatment for neuropathic pain and is indicated for pain of postherpetic neuralgia. Typically, 5% patches are used: 12 hours on and 12 hours off daily. Side effects are minimal, with the exception of local irritation and possible hypersensitivity. In multiple small, class III clinical studies, there was dramatic improvement compared with placebo.[74,75] These studies were small, and there was no comparison to other accepted therapies. Based on current available evidence, lidocaine patches are possibly effective, and can be considered for treatment of neuropathic pain.[13]

Clonidine is an α2-adrenergic receptor agonist. Trial results regarding its use in neuropathic pain have been mixed, with it probably being effective as adjunctive therapy in patients with neuropathic pain. While a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of 182 participants showed that 0.1% topical clonidine topical gel formulation, used at total daily dose of 3.9 mg/day, improved pain in patients suffering from painful diabetic neuropathy,[76] the Phase III trial ultimately failed to show a statistically significant difference. A two-phase, double-blind, crossover placebo-controlled study showed that a clonidine patch, started at 0.1 mg/day and titrated up to either to the maximum dose of 0.3 mg/day or decreased to a tolerable dose, did show a statistically significant decrease in the pain intensity associated with painful diabetic neuropathy. Post hoc analysis suggested that patients with intermittent, sharp, and shooting pain sensations may receive the greatest benefit. Clonidine patches are administered weekly at doses of 0.1, 0.2, and 0.3 mg/day.[77]

EMLA (eutectic mixture of local anesthetics) is a 1:1 mixture of prilocaine and lidocaine, which can penetrate the skin and produce local anesthesia. It has been helpful in patients with peripheral nerve lesions and in reducing pain associated with venipuncture. EMLA has been particularly helpful in postherpetic neuralgia.[78]

There have been several small, randomized control trial studies showing the efficacy of topical botulinum toxin for neuropathic pain.[79–81] The underlying mechanism is thought to be through botulinum toxin type A's effect on the presynaptic vesicles of neurons, inhibiting the release of certain neurotransmitters involved in pain, as well as its inhibition of the expression of vanilloid receptor TRPV1 on the surface of peripheral nociceptors.[82,83] In the aforementioned studies, all patients were randomized to either botulinum toxin treatment or saline injections, and then crossed over to the alternative treatment. All studies found statistical significance in pain reduction following botulinum toxin treatment compared with placebo. Yuan et al[80] found statistically significant improvement in VAS scores up to 12 weeks of posttreatment, and Ranoux et al[79] found statistically significant improvement in Brief Pain Inventory scores up to 14 weeks of posttreatment. These studies are small but promising. Further studies on larger groups are currently underway.[84] Until completed, its use remains experimental.